AN INTEGRATED DESIGN FOR DOSE COMPARISON TRIALS

An integrated design, which incorporates the dose titration scheme int o the parallel comparative design, is proposed for dose comparison tri als of drugs that may cause a first-dose phenomenon. This design inclu des a concurrent placebo control group, thereby providing valid estima te of drug effect. The other groups are defined by the maximum allowab le dose. Except for the maximum allowable dose, both the titration sch edule and the titration interval are standardized. The effect of the p ace of titration is thus controlled. In extreme cases, all patients ne ed only the lowest dose tested, and all patients need the highest dose tested to achieve the required efficacy response. In nonextreme cases , this design answers questions that are usually asked of dose compara tive trials: overall drug effects, adequacy of starting dose, effects of dose increment, maximum effective dose, dose-response relationship, and time effect. Because both efficacy and safety analyses can be per formed similarly, risk-benefit analysis thus can be evaluated in the s ame group of patients, and an optimum titration regimen may be determi ned rationally.